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Series GSE173667 Query DataSets for GSE173667
Status Public on Jun 18, 2021
Title Heterozygous OAS1 Gain-of-Function Variants Cause a Polymorphic Autoinflammatory and Immunodeficiency Syndrome
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Oligoadenylate synthase 1 (OAS1) is a type-1 interferon-inducible, intracellular double-stranded RNA (dsRNA) sensor that generates 2'-5'-oligoadenylate (2-5A) to activate RNaseL as a means of antiviral defense. We report four de novo heterozygous OAS1 variants in five patients. Variant OAS1 proteins show dsRNA-independent gain-of-function 2-5A synthetase activity that results in RNaseL-mediated RNA-cleavage, transcriptomic downregulation, and functional impairment and/or apoptosis of monocytes, iPSC-derived macrophages, and B-cells. This leads to a polymorphic syndrome of monocyte, macrophage, and B-cell deficiency characterized by autoinflammation, pulmonary alveolar proteinosis, and hypogammaglobulinemia. RNase-L-inhibition in vitro mitigates, and hematopoietic cell transplantation in vivo corrects the autoinflammatory and immunodeficiency phenotype.
Overall design iPSC-derived macrophages, poly-A tailed mRNA isolation, library preparation and quantification were performed with NEBNext kits (New England Biolabs, Ipswich, USA) following manufacture’s instructions. Libraries were sequenced on a NextSeq 500 (Illumina, San Diego, USA)

Poly-A selection?based RNA sequencing (RNA-seq) was performed on FACS-sorted OAS1-WT (three different healthy donors (HD), HD1 and HD2 in duplicates) and A76V (in duplicates) CD14 monocytes, CD19 B cells, and CD3 T cells. Libraries were sequenced on a single lane in 100 bp single end mode on a HiSeq1500 instrument (Illumina, San Diego, USA).
Contributor(s) Magg T, Okano T, Koenig LM, Boehmer DR, Schwartz SL, Inoue K, Heimall J, Licciardi F, Ley-Zaporozhan J, Ferdman RM, Caballero-Oteyza A, Park EN, Calderon BM, Dey D, Kanegane H, Cho K, Montin D, Reiter K, Griese M, Albert MH, Rohlfs M, Gray P, Walz C, Conn GL, Sullivan KE, Klein C, Morio T, Hauck F
Citation(s) 34145065
Submission date Apr 30, 2021
Last update date Nov 20, 2021
Contact name Thomas Magg
Organization name Dr. von Haunersches Kinderspital der LMU München
Street address Lindwurmstr. 2a
City München
ZIP/Postal code 80337
Country Germany
Platforms (2)
GPL18460 Illumina HiSeq 1500 (Homo sapiens)
GPL18573 Illumina NextSeq 500 (Homo sapiens)
Samples (31)
GSM5273421 Ct1
GSM5273422 Ct1-IFNa
GSM5273423 Ct2
BioProject PRJNA726563
SRA SRP318036

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE173667_OAS1_CD3_CD14_CD19_counts.xlsx 2.4 Mb (ftp)(http) XLSX
GSE173667_OAS1_RNAseq_iPSC-derived_Macrophages_counts.xlsx 5.0 Mb (ftp)(http) XLSX
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Raw data are available in SRA
Processed data are available on Series record

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